Bethesda, Md., Sun. Dec. 14, 2008 —
An international consortium, in search of the genetic risk factors for obesity, has identified six new genetic variants associated with BMI, or body mass index, a measurement that compares height to weight. The results, funded in part by the National Institutes of Health (NIH), were published online in the journal Nature Genetics on December 14.

The effect of each individual genetic variant was modest and the authors state in the paper that their findings have uncovered only a small fraction of what are probably hundreds of regions in the human genome that are likely to have minor contributions to obesity. The paper estimates that the 1 percent of people harboring the most obesity-causing variants will be an average of 10 pounds heavier than the 1 percent of individuals with the fewest variants, and 4 pounds heavier than a typical person.

"Obesity is a major public health concern, with myriad health consequences. Understanding obesity's biological basis is crucial to designing more effective treatment and prevention strategies to help control body weight," said Alan E. Guttmacher, M.D., acting director of the National Human Genome Research Institute (NHGRI). "Today's findings are a major step forward in understanding how the human body regulates weight."

The study, conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium representing 76 international research organizations, was led by Joel Hirschhorn, M.D., Ph.D. of Children's Hospital Boston and the Broad Institute of Harvard and MIT and Gonçalo R. Abecasis, Ph.D. of the University of Michigan's School of Public Health. Coauthors included intramural researchers from the National Human Genome Research Institute, the National Institute of Aging and the National Cancer Institute, all part of the NIH.

A large body of scientific evidence shows that obesity can predispose people to a variety of health problems, including diabetes, some cancers, stroke, high blood pressure and coronary heart disease. It is estimated that nearly one third of adults in the U.S. are considered obese, having a BMI of 30 or more. Genes regulate the fat storing biological pathways in the body and these clearly vary among individuals. Obesity is also associated with more than 100,000 deaths each year in the U.S. population.

The research team tested and compared BMI data and genetic information from more than 32,000 individuals of European ancestry pooled from 15 genome-wide association studies identifying, in the end identifying 35 genetic variants. These genetic variants were further tested for validation in more than 50,000 additional individuals, also of European ancestry.

Genetic variants in six genes (TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1) were shown to be strongly associated with BMI. Four of the genetic variants were found to be associated with both adult and childhood obesity. In addition, the research team confirmed the association of variants in two genes (FTO and MC4R) that had previously been associated with BMI last year.

All six of the genetic variants were found to be activated in the central nervous system, specifically the brain and hypothalamus. Prior studies have demonstrated the role of the central nervous system in body weight regulation, including on appetite, energy expenditure and other behavioral aspects.

In addition, the research team compared their results with a large genome-wide association study of BMI, led by deCODE Genetics in Iceland, which has an accompanying paper in the same issue of Nature Genetics. Where comparisons could be made, five of the genetic variants were confirmed in both data sets.

The GIANT researchers also compared their results to genome-wide association studies for known obesity complications, including type 2 diabetes, lipid levels, and coronary artery disease and found two of the genetic variants (in the GNPDA2 and TMEM18 genes) were associated with type 2 diabetes.

These results are intriguing and consistent with outcomes from family and twin studies which suggest that genetic factors may account for as much as 40 to 70 percent of BMI variation in the general population.

"We know that environmental factors, such as diet, play a role in obesity, but this research further provides evidence that genetic variationplays a significant role in an individual's predisposition to obesity, " said Eric D. Green, M.D., Ph.D., NHGRI scientific director. "It will be important to see what this team uncovers in follow-up studies and how this breakthrough contributes to our knowledge of the biology of human weight."

The GIANT consortium is currently pursuing large-scale studies to identify more genetic variants contributing to the risk of obesity y in both adults and children. They hope to expand the study to examine the genetic information from more than 100,000 people providing them with more statistical power for their findings. Additionally, they plan to study different ethnic populations as well as comparing people with extreme obesity to overweight and normal individuals.

In addition to NHGRI, NIA, and NCI, other NIH institutes who contributed funding to the study include the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Heart Lung and Blood Institute (NHLBI), and the National Institute of Mental Health (NIMH).

NHGRI, NIA, NCI, NIDDK, NHLBI and NIMH are six of the 27 institutes and centers at the National Institutes of Health, which is an agency of the Department of Health and Human Services.

The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at www.genome.gov.

The NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people. For more information on research and aging, go to www.nia.nih.gov.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The NIDDK conducts and supports research in diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. Additional information about NIDDK can be found at www.niddk.nih.gov.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH Web site.

The National Institutes of Health - The Nation's Medical Research Agency - includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit www.nih.gov.